In 1990 we identified a child with a disorder involving dramatic enlargement of all her lymph node chains, hepatomegaly, splenomegaly, autoimmune hemolytic anemia and marked expansion of CD3+/CD4-/CD8- T cells. We have termed this disorder autoimmune lymphoproliferation syndrome, or ALPS. We subsequently indentified one or more members of 18 families with similar disorder; their clinical an dimmunologic features were well-studied. Heritable, functional mutations in the gene encoding Fas, a cell surface protein involved in lymphocyte apoptosis, were identified in 14 of the families, in both patients and in unaffected relatives; 4 ALPS patients have no mutations in Fas or its ligand. Defective T and B cell apoptosis was demonstrated for all subjects. Detailed analysis of immune function shows ALPS patients to exhibit a predominant Th2 cytokine profile, with markedly elevated circulating IL-10 and decreased monocyte release of IL-12. This is the first genetic disorder involving apoptosis and the first gene in which a defect leads to human autoimmune disease. With this expanding number of affected families, we hare recognizing an expanded clinical spectrum of the Syndrome and we are conducting further genetic and family studies to define factors that contribute to more sever disease expression. We are currently analyzing other proteins related to apoptosis to determine whether they contribute to ALPS.